In a 20-year prospective study on British doctors, smoking habits were ascertained by questionnaire and lung cancer incidence was monitored. Among cigarette smokers who started smoking at ages 16-25 and who smoked 40 or less per day, the annual lung cancer incidence in the age range 40-79 was:0.273X10(-12). (cigarettes/day+6)2. (age--22.5)4.5. The form of the dependence on dose in this relationship is subject not only to random error but also to serious systematic biases, which are discussed. However, there was certainly some statistically significant (P less than 0.01) upward curvature of the dose-response relationship in the range 0-40 cigarettes/day, which is what might be expected if more that one of the "stages" (in the multistage genesis of bronchial carcinoma) was strongly affected by smoking. If a higher than linear dose-response relationship exists between dose per bronchial cell and age-specific risk per bronchial cell, this may help explain why bronchial carcinomas chiefly arise in the upper bronchi, for dilution effects might then protect the larger areas lower in the bronchial tree.

https://jech.bmj.com/content/jech/32/4/303.full.pdf

Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers.

The effect of ionising radiation is influenced by the dose, the dose rate, and the quality of the radiation. Before 1990, dose-equivalent quantities were defined in terms of a quality factor, Q(L), that was applied to the absorbed dose at a point in order to take into account the differences in the effects of different types of radiation. In its 1990 recommendations, the ICRP introduced a modified concept. For radiological protection purposes, the absorbed dose is averaged over an organ or tissue, T, and this absorbed dose average is weighted for the radiation quality in terms of the radiation weighting factor, wR, for the type and energy of radiation incident on the body. The resulting weighted dose is designated as the organ- or tissue-equivalent dose, HT. The sum of the organ-equivalent doses weighted by the ICRP organ-weighting factors, wT, is termed the effective dose, E. Measurements can be performed in terms of the operational quantities, ambient dose equivalent, and personal dose equivalent. These quantities continue to be defined in terms of the absorbed dose at the reference point weighted by Q(L). The values for wR and Q(L) in the 1990 recommendations were based on a review of the biological and other information available, but the underlying relative biological effectiveness (RBE) values and the choice of wR values were not elaborated in detail. Since 1990, there have been substantial developments in biological and dosimetric knowledge that justify a re-appraisal of wR values and how they may be derived. This re-appraisal is the principal objective of the present report. The report discusses in some detail the values of RBE with regard to stochastic effects, which are central to the selection of wR and Q(L). Those factors and the dose-equivalent quantities are restricted to the dose range of interest to radiation protection, i.e. to the general magnitude of the dose limits. In special circumstances where one deals with higher doses that can cause deterministic effects, the relevant RBE values are applied to obtain a weighted dose. The question of RBE values for deterministic effects and how they should be used is also treated in the report, but it is an issue that will demand further investigations. This report is one of a set of documents being developed by ICRP Committees in order to advise the ICRP on the formulation of its next Recommendations for Radiological Protection. Thus, while the report suggests some future modifications, the wR values given in the 1990 recommendations are still valid at this time. The report provides a scientific background and suggests how the ICRP might proceed with the derivation of wR values ahead of its forthcoming recommendations.

https://journals.sagepub.com/doi/pdf/10.1016/S0146-6453%2803%2900024-1

Relative biological effectiveness(RBE), quality factor(Q), and radiation weighting factor(WR)

1. Quantitative Radiation Biology.- 1.1 Radiation in Society.- 1.2 Radiation Biology: the Interdisciplinary Discipline.- 1.3 The Importance of Cellular Biology.- 1.4 The Quantitative Analysis of Radiation Action: a Brief Historical Review.- 1.5 Desiderata for a Quantitative Theory of Radiation Biology.- 2. The DNA Molecule and Its Role in the Cell.- 2.1 Introduction.- 2.2 The Structure and Dimensions of the DNA Molecule.- 2.3 Base Sequences and the Genetic Code.- 2.4 DNA Replication.- 2.5 DNA in Chromosomes.- 2.6 The Diploid Cell, Mitosis and Meiosis.- 2.7 Radiation-Induced Damage to DNA.- 2.7.1 DNA Base Damage.- 2.7.2 DNA Single Strand Breaks.- 2.7.3 DNA Double Strand Breaks.- 3. The Molecular Model for Cell Survival Following Radiation.- 3.1 Historical Development.- 3.2 The Philosophical Framework of the Model.- 3.3 The Induction of DNA Double Strand Breaks by Radiation.- 3.3.1 The Induction of DNA Single Strand Breaks.- 3.3.2 The Induction of DNA Double Strand Breaks in One Radiation Event.- 3.3.3 The Induction of DNA Double Strand Breaks in Two Radiation Events.- 3.3.4 The Total Induction of DNA Double Strand Breaks.- 3.3.5 The Induction of DNA Double Strand Breaks with Repair.- 3.3.6 The Influence of Base Damage on the Production of Double Strand Breaks.- 3.4 The Relationship Between Cell Survival and DNA Double Strand Breaks.- 3.5 The Cell Survival Curve.- 3.5.1 Cell Survival as Criterium.- 3.5.2 Correction for Cell Multiplicity.- 3.5.3 The Shape of the Cell Survival Curve.- 3.5.4 The Analysis of Experimental Data.- 3.6 Variation in the Survival Curve Through the Cell Cycle.- 3.7 Asynchronous Cell Populations.- 3.8 The Experimental Correlation Between Cell Survival and DNA Double Strand Breaks.- 3.9 Summary.- 4. Chromosomal Aberrations.- 4.1 Introduction.- 4.2 The Nature and Yield of Chromosomal Aberrations.- 4.3 The Classical and Exchange Theories of Radiation- Induced Chromosomal Aberrations.- 4.3.1 The Classical Theory.- 4.3.2 The Exchange Theory.- 4.3.3 The Problem.- 4.4 The Molecular Theory of Radiation-Induced Chromosomal Aberrations.- 4.4.1 The Yield of Chromosomal Aberrations.- 4.4.2 The Formation of Chromosomal Aberrations by the Process of Telomere-Break Rejoining.- 4.4.2.1 A Possible Molecular Mechanism for Rejoining Between a Telomere and a Break and the Stabilization of a Broken End.- 4.4.3 The Formation of Chromosomal Aberrations by the Process of Recombinational Rejoining.- 4.4.3.1 Repetitive DNA.- 4.4.3.2 Palindromes.- 4.4.3.3 Incompleteness.- 4.4.4 The Experimental Evidence for Telomere-Break Rejoining.- 4.4.4.1 The Haplopappus Experiment.- 4.4.4.2 Other Radiation Experiments.- 4.4.4.3 Medical Cytology.- 4.4.5 The Experimental Evidence for the Process of Recip--rocal Recombination.- 4.4.6 Two Mechanisms for the Formation of Chromosomal Aberrations?.- 4.4.6.1 The Molecular Nature of the Telomere.- 4.4.6.2 The Role of Caffeine.- 4.5 Complex Chromosomal Rearrangements.- 4.6 Gene Transplantation.- 4.7 Summary.- 5. Somatic Mutations.- 5.1 Point and Chromosome Mutations.- 5.2 Some Molecular Mechanisms Which Could Give Rise to Mutations from DNA Double Strand Breaks.- 5.2.1 The Rejoining of Single Stranded Tails.- 5.2.2 Resnick's Model for Gene Conversion.- 5.2.3 Resnick's Model for Reciprocal Recombination.- 5.2.4 Rejoining Between a Telomere and a Single Stranded Tail.- 5.2.5 No Repair.- 5.2.6 The Repair Processes and Mutation Induction.- 5.3 Mutation Frequency Dose Relationships.- 5.3.1 The Induction of Mutations.- 5.3.2 The Suppression of Mutation Expression.- 5.3.3 The Influence of Cell Killing.- 5.4 The Analysis of Experimental Data.- 5.5 Two Mutations in the Same Cell Population.- 5.6 The Mutation Spectrum.- 5.7 Summary.- 6. Correlations.- 6.1 Introduction.- 6.2 The Survival-Survival Correlation.- 6.3 The Survival-Chromosomal Aberration Correlation.- 6.4 The Correlation Between Different Chromosomal Aberrations.- 6.5 The Correlation Between "Normal" Chromosomal Aberrations and "Complex" Chromosomal Aberrations.- 6.6 The Correlation Between Survival and Somatic Mutation.- 6.7 The Correlation Between Two Different Mutations Induced in the Same Cell Population.- 6.8 The Peak Incidence - an Implied Correlation.- 6.9 What Do the Correlations Mean?.- 7. Repair.- 7.1 Introduction.- 7.2 The Repair of DNA Single Strand Breaks and the Dose Rate Effect.- 7.2.1 Experimental Evidence on DNA Single Strand Break Repair.- 7.2.2 The Time Scale of the Three Dose Rate Regions.- 7.2.3 The Exponential Repair of DNA Single Strand Breaks and Its Effect on the Dose Response Relationships.- 7.2.4 Implications for the InS/D Versus D Analysis.- 7.2.5 Complicated Repair Rates.- 7.2.6 Practical Difficulties in the Determination of Dose-rate Effects.- 7.3 The Repair of DNA Single Strand Breaks and the Effect of Dose Fractionation.- 7.3.1 The Analysis of Repair Using Fractionation Studies.- 7.4 The Repair of DNA Double Strand Breaks and the Post-Irradiation Effect.- 7.4.1 The Quantitative Effect of DNA Double Strand Break Repair on Cell Survival.- 7.4.1.1 The Time Dependence of the Repair of DNA Double Strand Breaks.- 7.4.2 The Quantitative Effect of DNA Double Strand Break Repair on Chromosomal Aberration Yield.- 7.4.3 The Quantitative Effect of DNA Double Strand Break Repair on Mutation Frequency.- 7.4.4 Is the Efficiency for the Repair of DNA Double Strand Breaks Always Dose-independent?.- 7.5 The Difference Between Sub-lethal Damage Repair and Potentially Lethal Damage Repair.- 8. Radiation Quality.- 8.1 The Differing Shape of Dose-response Relationships.- 8.2 A Qualitative Assessment of the Dependence of the ?-Coefficient on Radiation Quality.- 8.3 A Qualitative Assessment of the Dependence of the ?-Coefficient on Radiation Quality.- 8.4 How Constant is the Value of RBEo?.- 8.4.1 The Variation of RBEo in the Cell Cycle.- 8.4.2 The Effect of Different Conditions in the Cell.- 8.4.3 Extremely High Values of RBEo.- 8.5 The Size of the Target.- 8.6 A Calculation of the Dependence of the a- and ss- Coefficients on Radiation Quality.- 8.6.1 The Track Model.- 8.6.2 A Calculation of the Induction of DNA Single and Double Strand Breaks.- 8.6.3 A Quantitative Assessment of the Dependence of Cell Survival on Radiation Quality.- 8.6.4 The Relation Between Physics, Chemistry, and Biology.- 8.7 Summary.- 9. Cancer.- 9.1 Introduction.- 9.2 Somatic Mutation and Cancer.- 9.2.1 Historical Development.- 9.2.2 The Modern Evidence Supporting the Somatic Mutation Theory.- 9.2.2.1 The Mutagen Screening Tests.- 9.2.2.2 The Typical Chromosomal Aberrations.- 9.2.2.3 The Repair-deficient Human Disorders.- 9.3 The Malignant Cell.- 9.4 Radiation-Induced Cell Transformation.- 9.4.1 The Diploid Carrier Cell.- 9.4.2 The Tetraploid Carrier Cell.- 9.4.3 The Diploid Non-Carrier Cell.- 9.5 Extrapolation to Animals and Man.- 9.5.1 Experimental Data for Animals.- 9.5.2 Radiation-induced Malignancy in Man.- 9.5.2.1 Sparsely Ionizing Radiation.- 9.5.2.2 Densely Ionizing Radiation.- 9.6 Conclusion.- 10. Genetic Effects.- 10.1 Introduction.- 10.2 The Induction of Dominant Lethal Mutations.- 10.3 Correlations Between Different Genetic End Points.- 10.3.1 The Correlation Between Dominant Lethality and the Yield of Chromosomal Aberrations.- 10.3.2 The Correlation Between Different Chromosomal Aberrations.- 10.3.3 The Correlation Between Dominant Visible Mutations and Specific Locus Mutations in the Mouse.- 10.3.4 The Correlation Between Dominant and Recessive Lethal Mutations.- 10.4 The Induction of Translocations in the Spermatogonia of the Mouse.- 10.4.1 The Spermatogonial Stem Cell Development.- 10.4.2 Acute Irradiation.- 10.4.3 The Effect of Dose Rate.- 10.4.4 Short-Term Fractionation.- 10.4.5 Twenty-Four-Hour Fractionation.- 10.4.6 Long-Term Fractionation.- 10.5 The Induction of Specific Locus Mutations in the Mouse.- 10.6 Conclusions.- 11. Synergistic Interaction.- 11.1 Introduction.- 11.2 Theoretical Development.- 11.3 Agent Toxicity.- 11.4 Agent Dosimetry.- 11.5 Experimental Examples of Synergism.- 11.5.1 The Interaction of Radiation with UV.- 11.5.2 The Interaction of Radiation with Halogenated Pyrimidine Analogues.- 11.5.3 The Interaction of Radiation with Nitrosourea Compounds.- 11.5.4 The Interaction of Radiation with Diamide.- 11.6 General Discussion.- 12. Implications.- 12.1 Radiological Protection.- 12.1.1 Sparsely Ionizing Radiation.- 12.1.2 Densely Ionizing Radiation.- 12.1.3 Cancer as a Recessive Genetic Character.- 12.1.4 Genetic Effects.- 12.1.5 The Effect of Environmental Mutagens.- 12.2 The Chemical Hazard.- 12.3 Radiation Therapy.- 12.3.1 Fractionation.- 12.3.1.1 ?-Type Sensitizer.- 12.3.1.2 ?-Type Sensitizer.- 12.3.1.3 Implications for the Choice of Sensitizer.- 12.4 Plant Mutation Breeding.- 12.5 Postscript.- References.- List of Abbreviations.

The Molecular Theory of Radiation Biology

Mortality was studied in 14 111 patients with ankylosing spondylitis given a single course of x-ray treatment during 1935-54. Mortality from all causes combined was 66% greater than that of members of the general population of England and Wales. There were substantial excesses of deaths from non-neoplastic conditions, but these appeared to be associated with the disease itself rather than its treatment. A nearly fivefold excess of deaths from leukaemia and a 62% excess of deaths from cancers of sites that would have been in the radiation fields ("heavily irradiated sites") were likely to have been a direct consequence of the radiation treatment itself. The excess death rate from leukaemia was greatest three to five years after treatment and was close to zero after 18 years. In contrast, the excess of cancers of heavily irradiated sites did not become apparent until nine or more years after irradiation and continued for a further 11 years. More than 20 years after irradiation the excess risk declined, but the fall was not statistically significant. The number of cancers of sites not considered to be in the radiation beams was 20% greater than expected. This excess, although not statistically significant, may also have been due to radiation scattered from beams directed at other parts of the body. The risk of a radiation-induced leukaemia or other cancer was related to the age of the patient at the time of treatment. Those irradiated when aged 55 years or more had an excess death rate from leukaemia more than 15 times that of those treated under 25 years of age, and a similar difference was apparent for cancers of heavily irradiated sites. The radiation dose to the bone marrow was estimated for the patients who died with leukaemia and for a 1 in 15 sample of the total study population. The excess risk of leukaemia varied erratically with radiation dose owing, perhaps, in part to the increase in the proportion of the cells in the bone marrow that are sterilised with increasing doses. A mathematical model using a linear leukaemia induction rate and exponential cell sterilisation fitted the data reasonably well, and the results suggested that for low radiation doses about two deaths from leukaemia would be induced per million people per rad of x rays per year for up to 20 years after exposure. Because of the failure to find a clear dose-response relationship this estimate must be regarded with caution, but it is in reasonable agreement with that derived from studies of the atomic bomb survivors.

/pdf/mortality-among-patients-with-ankylosing-spondylitis-after-a-4uvjjvylsv.pdf

Mortality among patients with ankylosing spondylitis after a single treatment course with x rays.

Radioiodine ((131)I) therapy of benign thyroid diseases was introduced 70 yr ago, and the patients treated since then are probably numbered in the millions. Fifty to 90% of hyperthyroid patients are cured within 1 yr after (131)I therapy. With longer follow-up, permanent hypothyroidism seems inevitable in Graves' disease, whereas this risk is much lower when treating toxic nodular goiter. The side effect causing most concern is the potential induction of ophthalmopathy in predisposed individuals. The response to (131)I therapy is to some extent related to the radiation dose. However, calculation of an exact thyroid dose is error-prone due to imprecise measurement of the (131)I biokinetics, and the importance of internal dosimetric factors, such as the thyroid follicle size, is probably underestimated. Besides these obstacles, several potential confounders interfere with the efficacy of (131)I therapy, and they may even interact mutually and counteract each other. Numerous studies have evaluated the effect of (131)I therapy, but results have been conflicting due to differences in design, sample size, patient selection, and dose calculation. It seems clear that no single factor reliably predicts the outcome from (131)I therapy. The individual radiosensitivity, still poorly defined and impossible to quantify, may be a major determinant of the outcome from (131)I therapy. Above all, the impact of (131)I therapy relies on the iodine-concentrating ability of the thyroid gland. The thyroid (131)I uptake (or retention) can be stimulated in several ways, including dietary iodine restriction and use of lithium. In particular, recombinant human thyrotropin has gained interest because this compound significantly amplifies the effect of (131)I therapy in patients with nontoxic nodular goiter.

Radioiodine Therapy in Benign Thyroid Diseases: Effects, Side Effects, and Factors Affecting Therapeutic Outcome

ABOUT two-thirds of the excess leukaemia in adult Japanese survivors of the atomic bombs is myeloid in type (acute plus chronic)1. Nevertheless, most of the extensive experimental work on leukaemia induction by ionising radiation in the past 25 yr has been concerned with the thymic leukaemia of the laboratory mouse2, a disease which may have no human counterpart. So far, only one series of systematic experiments has been reported on myeloid leukaemia in irradiated mice3,4, and this concerned RF mice, a strain which has this disease in the relatively high frequency of 2–6% in unirradiated controls. Single brief whole-body X-ray exposures have now proved to be effective in inducing myeloid leukaemia in male CBA/H mice, provided that the radiation dose is not too great. This possibly provides an important model for quantitative investigation of carcinogenic mechanisms and for use in the development of chemotherapy for the analogous human disease.

Myeloid leukaemia in x-ray irradiated CBA mice.

DALE et al.1 showed that carboxypolypeptidase could be protected in vitro against X-radiation by a variety of substances. One of these, thiourea, is shown below to reduce the mortality following whole-body irradiation of mice. We also tried a few other substances, selected, like thiourea, in the hope that they would enter cells without being too toxic or too rapidly metabolized, and would protect by competing for hydroxyl radicals. The effect of sodium ethane-dithiophosphonate is of added interest because sodium ethane-monothiophosphonate protects weakly against the radiomimetic substance bis-chlorethyl sulphide (mustard gas)2.

Reduction in lethal effect of x-radiation by pretreatment with thiourea or sodium ethane dithiophosphonate.

Shortening of life by chronic irradiation: the experimental facts.

Chronic Radiation Hazards: An Experimental Study with Fast Neutrons

Differential Distribution of Radioactive Strontium and Yttrium in the Tissues of the Rabbit's Eye

R. H. Mole

Papers

Myeloid leukaemia in x-ray irradiated CBA mice.

Reduction in lethal effect of x-radiation by pretreatment with thiourea or sodium ethane dithiophosphonate.

Shortening of life by chronic irradiation: the experimental facts.

Chronic Radiation Hazards: An Experimental Study with Fast Neutrons

Differential distribution of radioactive strontium and yttrium in the tissues of the rabbit's eye.